Reactions that interconvert strong covalent bonds, termed “dynamic covalent chemistry” (DCC), offer a powerful approach for thermodynamically controlled synthesis of organic molecules with interesting structures and/or properties. DCC involving esters, thioesters, imines and disulfides, among other functional groups, has provided access to useful new molecules and molecular insights. Such efforts to date have focused on bonds that were previously known to be readily exchangeable. Extension of the DCC approach to other types of functional groups will require advances in organic reactivity and catalysis. It would be valuable, for example, to implement DCC with carboxamide-containing molecules, but the low intrinsic reactivity of the carboxamide group has hampered efforts to achieve this goal. Identifying catalysts that induce amide metathesis, i.e., the interconversion of carboxamides based on cleavage and formation of the N-acyl bonds [(Eq. 1)], represents a fundamental challenge in organic reactivity. The inventors recently described metal-catalyzed transamidation reactions [(Eq. 2)], which, in principle, offer a pathway to amide metathesis. Subsequent studies, however, revealed that secondary amide metathesis is not successful under the original transamidation conditions.

One of the few previous examples of amide metathesis involves the use of proteases under conditions compatible with both peptide hydrolysis and synthesis. Limitation associated with these reactions include limited substrate scope and long reaction times.
As can be appreciated, there is a long felt need in the chemical arts for methods and reagents, such as small-molecule catalysts, that facilitate secondary amide metathesis. Such desirable technologies would certainly broaden the practical applications of dynamic covalent chemistry.